BME PhD Prospectus Defense - Kirk Pierce

Title: “Developing a Ubiquitin-Independent Platform for Targeted Protein Degradation with Applications in Hepatocellular Carcinoma”

Advisory Committee: Mark Grinstaff, PhD – BU BME, Chemistry, MSE, Medicine (Co-Advisor) Brian Snyder, MD, PhD – BIDMC Orthopedic Surgery (Co-Advisor) Mo Khalil, PhD – BU BME (Chair) Michael Albro, PhD – BU MechE, BME, MSE

Abstract: Many proteins known to be key mediators of disease phenotypes remain ‘undruggable’ by conventional therapeutics due to smooth interacting surfaces or intrinsically disordered structures. Recently, proteolysis targeting chimeras (PROTACs) have gained considerable attention as a drug class that can catalytically degrade proteins through the cell’s ubiquitin-proteasome system, promising a fully post-translational approach that will expand the number of potentially druggable proteins while maintaining specificity for mutant or modified proteins. However, despite advantages in ligand selection, PROTACs have struggled to expand to novel protein targets, failing to reach highly potent protein classes like transcription factors. To create a more universal degradation framework, I propose the development of a protein-based, ubiquitin-independent platform for targeted protein degradation that leverages the large contact areas from protein-protein interactions and a mechanism that does not rely on accessible lysine residues to greatly expand the ability to target ‘undruggable’ proteins. To achieve this, I will first develop and optimize a ubiquitin-independent degrader using GFP-tagged proteins as a model system for facile screening. I will then demonstrate the extensibility of the platform to degrade native proteins in vitro and in vivo by targeting β-catenin, a transcription factor frequently implicated in the development of hepatocellular carcinoma.